The primary aim of this proposal is to initiate a Phase I clinical trial that will explore the safety and possible efficacy of a single intravenous injection of 90Y-humanized PAM4 IgG in pancreatic cancer patients. PAM4 is a monoclonal antibody directed against a unique epitope found on the human tumor-associated antigen, MUC1 that is well expressed in pancreatic cancer. The antibody does not react with normal pancreas and has limited reactivity with pancreatitis. Preclinical studies have shown that radiolabeled PAM4 is targeted to a high degree to pancreatic tumor xenografts, and 90Y-PAM4 is a highly effective therapeutic agent in these models. Very importantly, these preclinical studies show that 90Y-PAM4 can be combined with gemcitabine, the only FDA-approved chemotherapeutic agent for pancreatic cancer, to improve the therapeutic response of gemcitabine. Indeed, once this trial is completed, our primary objective will be to develop a treatment strategy for adding 90Y-hPAM4 to a standard gemcitabine treatment regimen. PAM4 has been humanized and this proposal is designed to initiate clinical studies with this antibody, radiolabeled with 111In for use in external scintigraphy as a surrogate for 90Y-hPAM4 that will be used in therapy. The clinical trial will be initiated within 6 months of funding, allowing time to complete the Points to Consider and obtain an IND. The trial is designed to first test a suitable protein dose for hPAM4 to be used in the next step of clinical testing, namely a determination of the maximum tolerated dose for 90Y-hPAM4. All patients will have a pre-therapy imaging/pharmacokinetic/dosimetry study performed with 111In-hPAM4 IgG. This study will be used to predict the behavior of the 90Y-hPAM4 IgG that will be given one-week later. All patients will be treated with 9xY-hPAM4 IgG, but in the first step, the 90Y-hPAM4 IgG will be fixed at a dose of 10 mCi/m2. Three dose cohorts are planned in the first step at 5 mg, 15 mg/m2 and 50 mg/m2. Once a suitable protein dose is selected, in the second step, escalation of the 90Y-hPAM4 radioactivity will proceed, starting at 15 mCi/m2 and escalating in 5 mCi/m2 increments until the MTD is determined. The trial design reflects early discussions with the FDA concerning an appropriate trial design for a new antibody. The trial will be conducted at the Garden State Cancer Center and Johns Hopkins University School of Medicine. CMMI will be responsible for monitoring the study's progress.